Vitamin a derivatives and methods of preparing the same



Patented Jan. 22, 1952 UNITED STATES PATENT OFFICE VITAMIN A DERIVATIVES AND METHODS OF PREPARING THE SAME Leonard Weisler, Rochester, N. Y., assignor, by

mesne assignments, to Eastman Kodak Company, Rochester, N. Y., a corporation of New Jersey No Drawing. Application April 27, 1948, Serial No. 23,628

prepare new compounds which possess vitamin These and other objects are accomplished .i

by this invention which, a preferred embodiment, includes subjecting p-ionone or a C18 ketone which is an isoprenolog of fl-ionone to a condensation reaction with cyanoacetic acid,

or an ester thereof, and. reducing the resulting nitrile or cyanoester with lithium aluminum hydride or aluminium hydride toan amine or alcohol amine compound. i I v In one aspect of this invention ,B-ionone :(compound I) is condensed with cyanoacetic acid to form B-io'nyliden acetonitrile (compound '11) which is then reduced with an aluminum-containing hydride to fi-ionylidene ethyl amine (compound III) in accordance with the following series of reactions:

REACTION -1 H 0 CH3" Compound 11 REACTION 2 Compoundll LlAlH CompoundlII Tn Reaction 2 water is added after compound IIa-nd lithium aluminum hydride have ceased reacting. V

Reaction 1 may be carriedou-t in the absence-oi a solvent but it is preferable to use a solvent such as benzene, toluene, petoleum ether, aceticacid, or propionic acid. It benzene is-used as the solvent a cyanoaci-dwill "be produced insteadcf compound II and this must be decarboxylated in a separate step. However, if glacial acetic acid is the solvent, decarboxylation takes placespom taneously. It :is preferred to react p-ionone with cyanoacetic acid in a solution of glacial acetic acid in the presence of small'dantities'of acetamide and ammonium acetate, which act as catalysts. Heat is applied over a period of several hours until the solvent and water formed during thereaction have evaporated. 'Theiesidiie is fi-ionylidene acetonitrile which may be further purified by dissolving in ether, washing with water and dilute sodium carbonate, and drying by the addition of magnesium sulfate. The ether may then be evaporated off to leave a ,re's'idue' of purified fiionylidene acetonitrile. The product may be" further purified by distillation" or emomatography.

In performing the reduction of Reaction 2, p-ionylidene acetonitrile is dissolved in ether and lithium aluminum hydride (LiAII-Ir') or aluminum hydride (AlHa) is added. A reaction takes place at room temperature. At the conclusion-of the reaction water is added and the ether-soluble ,fl-ionylidene ethyl amine separated from the aqueous mixture. The ether may be evaporated from the mixture to leave a residue of ,B-ionylidene ethyl amine. V

*In another aspect of this invention a (lis ketone (com-pound IV) which is an isoprenolog of 18- ionone is condensed with cyanoaceti-c acid, or an ester thereof, as in Reaction 1. These reactions are shown below:

By following the series of reactions disclosed Compound IV C H:

HaC CH:

CH; CHI C O O R CH=CH23=CHCH=CH( 3=C Compound VI GEN Reactions 3 and 4 may be carried out under the conditions previously specified for Reaction 1. The "C1a ketone of Reactions 3 and 4 may be prepared by subjecting fi-ionone to a Reformatsky reaction with a halocrotonate, dehydrating and saponifying the resulting product to produce fi-ionylidene crotonic acid. and reacting this acid with lithium methyl to produce the C18 ketone, or it may be prepared by condensing fi-ionone with ethyl bromoacetate in accordance with the Reformatsky reaction, dehydrating the resulting hydroxy ester, reducing the resulting ester with lithium aluminum hydride in ether solution to produce B-ionylidene ethanol, and oxidizing this alcohol in the presence of aluminum isopropoxide and an excess of acetone to produce the C18 ketone (compound IV Compound V is vitamin A nitrile and compound V1 is a cyanoester closely related to vitamin A. Both compounds V and VI are useful in vitamin A synthesis.

R in Reaction 4 may be hydrogen as in Example 3 or it may be an aromatic or aliphatic alcohol radical such as -CHa, C2H5, -C6H5, C1eI-I33, -C1aH3'7, -C7H'z, etc. As used herein the term alcohol radical is defined as the portion of an ester molecule derived from an alcohol. It is analogous to the term acyl radical which is the portion of an ester molecule derived from an acid.

Compound V may be reduced to vitamin A amine (compound VII) under the conditions of Reaction 2 in the following manner:

REACTION 5 Compoud V LiA1H| H C CH1 CH; CH;

Cm 6. II CH poun V Compound VII has been tested for biological activity and has been found to possess at least 2 of the biopotency of vitamin A.

above it is possible to convert p-ionone into a compound of the formula HrC CH:

in which X is either =CH--CH2NH2 or CH: =CH-CH=CHC=Y wherein Y is either =CHCH2NH2,

COOR

\CEN or =CH-CEN, R being hydrogen, an alkyl group, or an aryl group.

The following specific examples further illustrate the invention:

Example 1.Preparation of fi-ionylidene acetonitrile A mixture of 20 g. of fiionone, 8.5 g. of cyanoacetic acid, 40 cc. of glacial acetic acid, 1 g. of acetamide, and 1 g. of ammonium acetate was heated on an oil bath until the acetic acid solvent and water formed in the reaction began to distill from the mixture. The reaction mixture was then held at this distillation temperature for four hours. The residue was then dissolved in 60 cc. of ether and washed three times with 50 cc. of water in a separatory funnel. The ether solution was next washed with 50 cc. of dilute aqueous sodium carbonate. It was then dried over sodium sulfate. The ether was evaporated from the mixture to leave a residue of crude fiionylidene acetonitrile. This was purified by dissolving in 200 cc. of petroleum ether and running through an adsorption column packed with finely divided sodium aluminum silicate. The petroleum ether was evaporated to yield a purified residue of fi-ionylidene acetonitrile. This nitrile was characterized by ultraviolet adsorption maxima at 255 and 304 ml, with extinctions of 566 and 565, respectively.

5. Example .2..-Prepar.ation of p-ionylidene: ethg/Larinine Is-ienyndene; acetonitril' 0.5 ,g.')' wa dissolved in 5 m1.',of her and 2 1111 'a lithiumalmninum hydride (approximately "1 molar)" "was added at Gweketon l mbou dw a. 90%.m e, 1.118 m l wa d s ol e n--5 gl cia acet id wh p te n d exa qaqet fl cid.; 0. e. ammo iu ce t i an 1e- 1et-' amide. The; mixture wasrefluxed in an oil bath at- 160 ;for twpyhours, after which ml.,of et s id wa qwl s lle 0.1 hermuct was diss'olved in A0, cc pf ether, washed with 40 cc of water threeztirnes in a separatory funnel, washed again with 0.5 normal sodium hydroxide, and finally washedwitlr 20.. cc.v portions of water to, neutrality. The rether. solution was. driedrover sodium sulfate "and the "seiveneremoveu under nitrogen. The product showed a strong nitrile absorption" in the*mf'ra'red and had an ultraviolet, extinction of 405 with;.a-, maximum 311E350 m Thisproduct was further ,purified by: dissolvinainlw .cc. ,of p t le m ethe r ne througha column packed with finely divided sodium. aluminum silicate. Theultraviolet extinction coefiicientwas then 745.

Eagample -4 ;--Preparation of vitamin Amtrz'le ethyl acetate qmlzetone (compound IV) (fig, .021 mole) was dissolved in '60 ml; glacial acetic,acid whioli;ontained 2.0 g. of cyano ethyl acetate,"OB'gQof ammonium acetate and 0.3 g. of acetamide. The mixture was refluxed in an oil bath at 160 for two hours, after which 35 ml. of acetic acid was slowly distilled on. The product was dissolved in ml. of ether, washed three times with 50 m1. of water, once with 50 ml. of 0.5 normal sodium hydroxide, and finally with successive 50 ml. portions of water until neutrality was attained. The ether solution was dried over sodium sulfate and the solvent removed under nitrogen. The residue consisted of vitamin A nitrile ethyl acetate which had an ultraviolet extinction coefficient of 433 with a maximum at 375 mp.

Example 5.Vitamz'n A amine Vitamin A nitrile (0.5 g.) was dissolved in 50 ml. of ether to which was added 2 ml. of lithium aluminum hydride (1 molar). The mixture reacted with some refluxing. When the mixture ceased to reflux it was heated for an additional minute on the steam bath. Decomposition of the excess lithium aluminum hydride was accomplished with water. The ether layer was decanted to a separatory funnel in which it was washed with water to neutrality. It was then dried over sodium sulfate and the solvent removed under nitrogen without heat. The product (0.5 g.) showed an absence of the cyanide group in the infrared! had an ultraviolet ab;-

sorption maximum at 325 m x with" i 1 ltfimtel On treatment with at antim h atrichlorm this.

compound gave a reddish-purple color. A test for the primary amine grouping, using fi uorescein chloride, was positive. Whiletlie invention hadbeendescribed in considerable detail in the above examples and description, it will be understood that'modiflcations and variations therein may be effected without enar ihefi jq hes i i ma t rsin n eim b ijf ri iidefin d av-r a ren m m 93 'IIBW themed compo nd a sta c 2. The method of 'making a polyene amine which comprises refluxing Tin glacial acetic acid, a member selected from the group consisting of fCHe with acompound, selected. iro m. the class consisting of 'cyanoaceticacid and esters thereof and thereby causing condensation "of said. reactantsand autodecarboxylation of lthe condensation. product] to an unsaturated polyene nitrile. and} thereafter reacti'ng'in ethersolution, said unsaturated polyene nitrile with a compound selected from the group consisting of aluminum hydride and lithium aluminum hydride effective to reduce the nitrile group thereof to an amino group without otherwise changing the unsaturation of said decarboxylated condensation product, and hydrolyzing the product of said reacting with water.

3. The method of making a compound exhibiting substantial vitamin A biological activity, which method comprises refluxing in glacial acetic acid a compound of the formula with a compound selected from the class consisting of cyanoacetic acid and esters thereof and thereby causing condensation of said reactants and autodecarboxylation of the condensation product to vitamin A nitrile, and thereafter reacting, in ether solution, said vitamin A nitrile with a compound selected from the class consisting of aluminum hydride and lithium aluminum hydride and adding water to the product of said reacting, and thereby efiecting reduction of said vitamin A nitrile to vitamin A amine.

4. The method of making vitamin A amine which comprises refluxing in glacial acetic acid a compound of the formula mo on,

' on, v onoH=cH-c=oH-on=on-c= with cyanoacetic acid thereby causing condensation of said reactants and autodecarboxylation of the condensation product to vitamin A nitrile, and thereafter reacting, in ether solution, said vitamin'A nitrile with a compound selected from the group consisting of aluminum hydride and lithium aluminum hydride and adding water to the product of said reacting and thereby effectively causing reduction of said vitamin A nitrile to vitamin A amine.

5. The method of making a polyene amine which comprises refluxing, in glacial acetic acid, a member selected from the class consisting of H30 CH3 and H CH3 with cyanoacetic acid and thereby causing condensation of said member and said cyanoaoetic acid and autodecarboxylation of the condensation product to an unsaturated polyene nitrile, and thereafter reacting, in ether solution, said unsaturated polyene nitrile with a compound selected from the class consisting of aluminum hydride and lithium aluminum hydride and adding water to the product of said reacting and thereby reducing said polyene nitrile to the corresponding polyene amine.

6. The method of making a polyene amine which comprises refluxing, in glacial acetic acid,

a member selected from the class consisting of densation of said member and said cyanoacetic acid and autodecarboxylation of the condensation product to an unsaturated polyene nitrile,- and thereafter reacting said unsaturated polyene nitrile with lithium aluminum hydride in-ether solution and adding water to the product of said reacting and thereby reducing said polyene nitrile to the corresponding polyene amine.

LEONARD WEISLER.

REFERENCES CITED The following references are of record in the f le of this patent:

UNITED STATES PATENTS Date Number Name 2,150,154 Gope Mar. 14, 1939 2,176,018 Cope et a1 Oct. 10, 1939 2,369,158 Milas Feb. 13, 1945 2,381,882 Cupery Aug. 14, 1945 2,414,722 Cornwell Jan. 21, 1947 2,415,834 Milas Feb. 18, 1947 2,432,921 Milas Dec. 16, 1947 OTHER REFERENCES Finholt et al.: "J, Am. Chem. v01. 69, 199-1203 (May 1947). 

2. THE METHOD OF MAKING A POLYENE AMINE WHICH COMPRISES REFLUXING IN GLACIAL ACETIC ACID, A MEMBER SELECTED FROM THE GROUP CONSISTING OF 